Leniolisib: First Approval.

Leniolisib (JOENJA®) is an oral selective phosphoinositide 3-kinase-delta (PI3Kδ) inhibitor being developed by Pharming Group NV in-licensed from Novartis for the treatment of immunodeficiency disorders. In March 2023, leniolisib received its first approval for the treatment of activated PI3Kδ syndrome (APDS) in adult and paediatric patients 12 years of age and older. Leniolisib is also under regulatory review in European Union for the treatment of APDS. Development of leniolisib for the treatment of Sjögren's syndrome has been discontinued. This article summarizes the milestones in the development of leniolisib leading to this first approval for APDS.

Durvalumab: A Review in Extensive-Stage SCLC.

Durvalumab (IMFINZI®), a fully human monoclonal antibody against programmed cell death-ligand 1 (PD-L1), is approved for use in combination with etoposide and either carboplatin or cisplatin for the first-line treatment of patients with extensive-stage small cell lung cancer (ES-SCLC). In the pivotal phase III CASPIAN trial in previously untreated adults with ES-SCLC, the addition of durvalumab to chemotherapy for up to 4 cycles followed by maintenance durvalumab was associated with a significantly longer overall survival and a favourable hazard ratio for progression-free survival compared with chemotherapy alone for up to 6 cycles. A higher proportion of patients in the durvalumab plus chemotherapy group had an objective response compared with the chemotherapy alone group. The efficacy of durvalumab was also sustained with longer follow-up. Durvalumab in combination with etoposide and either carboplatin or cisplatin had a manageable tolerability profile in patients with ES-SCLC. Given the available evidence, durvalumab in combination with etoposide and either carboplatin or cisplatin represents a valuable treatment option for the first-line treatment of patients with ES-SCLC, and is an accepted standard of care option in this setting.

Small cell lung cancer (SCLC) is the most aggressive form of lung cancer; extensive-stage (ES) disease, which accounts for about two-thirds of all SCLC, is associated with high relapse rates and a poor prognosis. Expression of programmed cell death-ligand 1 (PD-L1) on both tumour cells and tumour-associated immune cells is an adaptive immune response that helps tumour cells avoid detection and subsequent elimination by the immune system. Durvalumab (IMFINZI^®) is a fully human monoclonal antibody against PD-L1, which blocks the interaction of PD-L1 with its receptors, thus enhancing anti-tumour immune responses. When used in combination with chemotherapy (etoposide and either carboplatin or cisplatin) in adults with untreated ES-SCLC, durvalumab prolonged overall survival compared with chemotherapy alone; the improvements in overall survival were also maintained with additional follow-up. The tolerability profile of durvalumab in combination with chemotherapy was manageable in patients with ES-SCLC. Durvalumab in combination with chemotherapy is an effective and valuable treatment option for previously untreated patients with ES-SCLC.

Encorafenib: A Review in Metastatic Colorectal Cancer with a BRAF V600E Mutation.

Encorafenib (Braftovi®) is an oral small molecule BRAF inhibitor used in combination with cetuximab for the treatment of adult patients with metastatic colorectal cancer (mCRC) with a BRAF V600E mutation, who have received prior systemic therapy. In a clinical trial in adults with BRAF V600E-mutated mCRC who had disease progression after one or two previous regimens (BEACON CRC), encorafenib plus cetuximab was associated with a significantly longer median overall survival (OS), a higher objective response rate (ORR) and longer median progression-free survival (PFS), compared with standard therapy. Encorafenib plus cetuximab had a manageable tolerability profile in BEACON CRC. Current evidence suggests that encorafenib plus cetuximab combination therapy is an important targeted regimen for patients with mCRC and a BRAF V600E mutation who have received prior therapy.

Imlifidase: First Approval.

Imlifidase (IdefirixTM), a cysteine protease derived from the immunoglobulin G (IgG)­degrading enzyme of Streptococcus (S.) pyogenes is being developed by Hansa Biopharma AB for treatment of transplant rejection and rare IgG-mediated autoimmune conditions. In August 2020, intravenous imlifidase received its first global approval in the EU for desensitization treatment of highly sensitized adult kidney transplant patients with positive crossmatch against an available deceased donor. Imlifidase is currently undergoing clinical evaluation for the prevention of kidney transplant rejection in the USA, Australia, France and Austria, and clinical development is underway for anti-glomerular basement membrane disease, and for Guillain-Barre syndrome in France, the UK and the Netherlands. This article summarizes the milestones in the development of imlifidase leading to this first approval for desensitization treatment of highly sensitized adult kidney transplant patients with positive crossmatch against an available deceased donor.

Mecapegfilgrastim in Chemotherapy-Induced Neutropenia: A Profile of Its Use in China.

Mecapegfilgrastim (HHPG-19K) is a long-acting pegylated recombinant human granulocyte-colony stimulating factor (rhG-CSF) that is administered subcutaneously as prophylaxis once per chemotherapy cycle as a weight-adjusted dose of 100 µg/kg or as a 6 mg fixed dose. It is approved in China to reduce the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer therapy associated with a clinically significant incidence of febrile neutropenia. In phase III trials, once per cycle prophylaxis with mecapegfilgrastim was more effective than placebo in reducing the incidence of grade ≥ 3 neutropenia in cycle 1 in patients with advanced non-small cell lung cancer and was more effective than filgrastim at reducing the mean duration of grade ≥ 3 neutropenia in cycle 1 in patients with breast cancer. The tolerability and safety profiles of mecapegfilgrastim were similar to those of filgrastim, with no unexpected adverse events (AEs); most adverse reactions in cycle 1 were mild or moderate in severity. Thus, mecapegfilgrastim is an effective and generally well tolerated treatment option for patients with non-myeloid malignancies receiving myelosuppressive chemotherapy, and extends the options available for managing chemotherapy-induced neutropenia in China.

Apalutamide: A Review in Non-Metastatic Castration-Resistant Prostate Cancer.

Apalutamide (marketed as Erleada®) is an oral non-steroidal next-generation selective inhibitor of the androgen receptor (AR), and is approved in several countries, including the USA and those of the EU, for the treatment of non-metastatic castration-resistant prostate cancer (nmCRPC). In men with nmCRPC who were receiving androgen-deprivation therapy (ADT) and had a high risk of metastases in SPARTAN, apalutamide significantly prolonged metastasis-free survival (MFS) compared with placebo, with consistent benefits demonstrated across subgroups. The addition of apalutamide to ongoing ADT significantly prolonged time to metastasis and progression-free survival (PFS) compared with placebo, and maintained health-related quality of life (HR-QOL). Apalutamide was generally well tolerated in SPARTAN, with fatigue being the most frequently reported adverse event. Given the available evidence, apalutamide with ongoing ADT represents an emerging treatment option for patients with nmCRPC who are at high risk of developing metastatic disease.

Glycopyrronium/Formoterol: A Review in COPD.

Glycopyrronium/formoterol (Bevespi Aerosphere®) is a fixed-dose combination of the long-acting muscarinic antagonist glycopyrronium bromide and the long-acting ß2-agonist formoterol fumarate delivered via a pressurized metered dose inhaler (pMDI) and formulated using co-suspension delivery technology. It is approved in the USA and EU for use as maintenance treatment in patients with chronic obstructive pulmonary disease (COPD) and in Japan to relieve symptoms in patients with COPD. In the PINNACLE trials in patients with moderate to very severe COPD, glycopyrronium/formoterol was associated with significantly greater improvements in lung function than its monocomponents and placebo at 24 weeks and its monocomponents and open-label tiotropium over 52 weeks. In the AERISTO trial, glycopyrronium/formoterol was non-inferior to umeclidinium/vilanterol dry powder inhaler for peak change in forced expiratory volume in 1 s (FEV1) within 2 h postdose, but not for the change in morning predose trough FEV1, over 24 weeks. Glycopyrronium/formoterol was generally well tolerated in patients with moderate to very severe COPD, with most adverse events (AEs) being of mild or moderate severity. Thus, glycopyrronium/formoterol pMDI formulated using co-suspension delivery technology is a useful new addition that extends treatment options for patients with COPD.

Entrectinib: First Global Approval.

Entrectinib (Rozlytrek®) is an oral selective inhibitor of the tyrosine kinases tropomyosin receptor kinases (Trk)A/B/C [encoded by the genes neurotrophic tyrosine receptor kinase (NTRK) 1, 2 and 3, respectively], c-ros oncogene 1 (ROS1) and anaplastic lymphoma kinase (ALK) with central nervous system (CNS) activity developed by Roche for the treatment of various solid tumours harbouring NTRK1/2/3 or ROS1 gene fusions. In June 2019, entrectinib received its first global approval in Japan, for the treatment of adult and paediatric patients with NTRK fusion-positive, advanced or recurrent solid tumours and is under regulatory review for the treatment of adult patients with ROS1-positive non-small cell lung cancer (NSCLC). Entrectinib is also under regulatory review in the USA (PDUFA date 18 August 2019) and EU [Priority Medicines (PRIME) designation] for NTRK-positive solid tumours and ROS1-positive NSCLC. This article summarizes the milestones in the development of entrectinib leading to this first global approval for solid tumours in Japan.

Siponimod: First Global Approval.

Siponimod (Mayzent®) is an oral selective sphingosine 1-phosphate receptor subtypes 1 and 5 (S1PR1,5) modulator being developed by Novartis Pharmaceuticals for the treatment of multiple sclerosis (MS) and intracerebral haemorrhage. In March 2019, siponimod received its first global approval in the USA, for the treatment of adults with relapsing forms of MS, including clinically isolated syndrome, relapsing-remitting disease and active secondary progressive disease. Siponimod is under regulatory review in the EU and Japan for secondary progressive MS. This article summarizes the milestone in the development of siponimod leading to this first global approval for MS in the USA.

Lenvatinib: A Review in Hepatocellular Carcinoma.

Lenvatinib (Lenvima®) is an oral small molecule inhibitor of multiple receptor tyrosine kinases, and is approved for the first-line treatment of patients with unresectable hepatocellular carcinoma (HCC) in the USA, EU, Japan and China. The approval of lenvatinib was based on results of the randomized, open-label, multinational, non-inferiority phase III REFLECT trial in patients with unresectable HCC, who had not received treatment for advanced disease. In REFLECT, lenvatinib was non-inferior, but not superior, to sorafenib (current standard of care) for overall survival (OS). However, lenvatinib was associated with significant improvements compared with sorafenib in terms of all secondary endpoints [higher objective response rate (ORR), and longer progression-free survival (PFS) and time to progression (TTP)]. Lenvatinib had a generally manageable tolerability profile in REFLECT, with the most common treatment-emergent adverse events being hypertension, diarrhoea, decreased appetite and decreased weight. Given its non-inferior efficacy to sorafenib and manageable tolerability profile, lenvatinib represents a long-awaited alternative option to sorafenib for the first-line systemic treatment of patients with unresectable HCC. Further clinical experience may be required to fully define the position of lenvatinib in this setting.

FKB327: An Adalimumab Biosimilar.

FKB327 (Hulio®) is a biosimilar of the reference monoclonal anti-TNFα antibody adalimumab, and is approved in the EU for use in the same indications as reference adalimumab. FKB327 has similar physicochemical and pharmacodynamic properties to those of reference adalimumab, and pharmacokinetic equivalence was shown in healthy volunteers and patients with moderate-to-severe rheumatoid arthritis (RA) despite methotrexate therapy. FKB327 demonstrated equivalent clinical efficacy to that of reference adalimumab in patients with moderate-to-severe RA, and similar tolerability, safety and immunogenicity profiles. Switching from reference adalimumab to FKB327 had no impact on efficacy, safety or immunogenicity.

Emapalumab: First Global Approval.

Emapalumab-Izsg (hereafter referred to as emapalumab) [Gamifant®] is a monoclonal antibody directed against interferon gamma that is available as an intravenous infusion. Emapalumab is being developed by Novimmune and Swedish Orphan Biovitrum for the treatment of haemophagocytic lymphohistiocytosis (HLH). In November 2018, emapalumab received its first global approval in the USA, for the treatment of paediatric (newborn and older) and adult patients with primary HLH, who have refractory, recurrent or progressive disease or intolerance to conventional HLH therapy. Emapalumab is under regulatory review in the EU for the treatment of primary HLH. This article summarizes the milestones in the development of emapalumab leading to this first global approval for HLH in the USA.

Guselkumab: A Review in Moderate to Severe Plaque Psoriasis.

Guselkumab (Tremfya®) is a human immunoglobulin G1 λ (IgG1λ) monoclonal antibody (mAb) that blocks the interleukin-23 (IL-23)-mediated signalling pathway and is the first in its class to be approved in adults with moderate to severe plaque psoriasis in several countries, including the USA and EU. In the VOYAGE trials, guselkumab was superior to placebo and to adalimumab at week 16 in terms of the proportion of patients achieving an Investigator Global Assessment (IGA) score of 0/1 and ≥ 90% improvement from baseline in Psoriasis Area and Severity index score (PASI 90 response), with benefits of guselkumab over adalimumab maintained at week 24. To date, the beneficial effects of guselkumab treatment in these trials were maintained for up to 2 years. Inadequate responders to ustekinumab who were then randomized to guselkumab in NAVIGATE showed better responses than those randomized to ustekinumab between weeks 28-40, with a significantly greater mean number of visits at which patients had IGA 0/1 and ≥ 2-grade improvement in IGA score, as well as higher proportions of patients achieving PASI 90 and PASI 100 at week 52. Treatment with guselkumab improved health-related quality of life (HR-QOL) and patient-reported outcomes in all trials and was generally well tolerated. Guselkumab, administered by subcutaneous injection, is a useful new option for patients with moderate to severe plaque psoriasis.

Correction to: PF-06438179/GP1111: An Infliximab Biosimilar.

The article PF-06438179/GP1111: An Infliximab Biosimilar, written by Zaina T. Al-Salama.

PF-06438179/GP1111: An Infliximab Biosimilar.

PF-06438179/GP1111 (Zessly®; Ixifi®) [hereafter referred to as GP1111] is a biosimilar of the reference monoclonal anti-TNF-α antibody infliximab, and is approved in the EU and USA for the same indications as the reference drug, including rheumatoid arthritis (RA), Crohn's disease, ulcerative colitis (including paediatric ulcerative colitis in the EU), ankylosing spondylitis, psoriatic arthritis and plaque psoriasis; GP1111 is also approved in Japan. GP1111 has similar physicochemical characteristics and pharmacodynamic properties to those of reference infliximab, and the pharmacokinetic similarity of the agents has been shown in healthy volunteers and patients with moderate-to-severe RA despite methotrexate therapy. GP1111 demonstrated clinical efficacy equivalent to that of reference infliximab in patients with moderate-to-severe RA, despite methotrexate therapy, and was generally well tolerated in this population. The tolerability, immunogenicity and safety profiles of GP1111 were similar to those of reference infliximab, and switching from reference infliximab to GP1111 had no impact on safety, efficacy or immunogenicity. The role of reference infliximab in the management of autoimmune inflammatory conditions is well established and GP1111 provides an effective biosimilar alternative for patients requiring infliximab therapy.

Inotuzumab Ozogamicin: A Review in Relapsed/Refractory B-Cell Acute Lymphoblastic Leukaemia.

The intravenous CD22-directed antibody drug conjugate inotuzumab ozogamicin (Besponsa®) is approved in several countries including in the USA, EU and Japan, as monotherapy for the treatment of adults with relapsed/refractory B-cell acute lymphoblastic leukaemia (ALL). In adults with relapsed/refractory B-cell ALL who had received one or two prior treatment regimens, inotuzumab ozogamicin was associated with significantly higher rates of complete remission (including complete remission with incomplete haematological recovery) [CR/CRi] than standard therapy in the pivotal INO-VATE ALL trial. Inotuzumab ozogamicin was associated with significantly longer progression-free survival (PFS), duration of remission and higher haematopoietic stem cell transplantation (HSCT) rates than standard therapy. Although there was no significant between-group difference in overall survival duration as per the study design, the 2-year survival probability in the inotuzumab ozogamicin arm was twice that in the control arm. Inotuzumab ozogamicin had an acceptable tolerability profile. Thus, inotuzumab ozogamicin is an important new treatment option for patients with relapsed/refractory CD22-positive B-cell ALL.

Baricitinib: A Review in Rheumatoid Arthritis.

Baricitinib (Olumiant®) is an oral, targeted synthetic DMARD that inhibits JAK1 and JAK2, which are implicated in the pathogenesis of rheumatoid arthritis (RA). This novel, small molecule is approved for use as monotherapy, or in combination with methotrexate, for the treatment of adults with moderate to severe active RA who responded inadequately to or were intolerant of ≥ 1 DMARD. In pivotal multinational trials, once-daily baricitinib 4 mg, with/without methotrexate (± another csDMARD), improved the signs and symptoms of RA, disease activity and physical function in DMARD-naive patients and in patients with an inadequate response to methotrexate, csDMARDs or TNF inhibitors; baricitinib treatment also slowed structural joint damage in DMARD-naive patients and in those with an inadequate response to methotrexate and csDMARDs. Baricitinib plus methotrexate was more effective than adalimumab plus methotrexate in patients with an inadequate response to methotrexate. The onset of these benefits was generally rapid and sustained over time. Baricitinib was generally well tolerated during up to 5.5 years' treatment; the most commonly reported adverse drug reactions were upper respiratory tract infections, increased LDL cholesterol, nausea and thrombocytosis. Thus, once-daily baricitinib, as monotherapy or in combination with methotrexate, is an effective and generally well tolerated emerging treatment for patients with moderate to severe active RA who have responded inadequately to or are intolerant of ≥ 1 DMARD, and extends the options available for this population.

Apalutamide: First Global Approval.

Apalutamide (ErleadaTM) is a next-generation oral androgen receptor (AR) inhibitor that is being developed by Janssen for the treatment of prostate cancer (PC). It binds directly to the ligand-binding domain of the AR and blocks the effects of androgens. In February 2018, apalutamide received its first global approval in the USA for the treatment of non-metastatic castration-resistant PC (nmCRPC). Apalutamide is undergoing phase III investigation in chemotherapy-naive patients with metastatic CRPC (in combination with abiraterone acetate plus prednisone), patients with high-risk localized or locally advanced PC receiving primary radiation therapy, and in patients with metastatic hormone-sensitive PC and biochemically-relapsed PC. This article summarizes the milestones in the development of apalutamide leading to this first approval in nmCRPC.

Correction to: Lonoctocog Alfa: A Review in Haemophilia A.

The article Lonoctocog Alfa: A Review in Haemophilia A, written by Zaina T. Al-Salama and Lesley J. Scott, was originally published Online First without open access. After publication in volume 77, issue 15, pages 1677-1686 CSL Behring GmbH requested that the article be Open Choice to make the article an open access publication. Post-publication open access was funded by CSL Behring GmbH. Further details may be found at http://www.medengine.com/Redeem/CBD8F060224F2E65 . The article is forthwith distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License ( http://creativecommons.org/licenses/by-nc/4.0/ ), which permits any noncommercial use, duplication, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.